{"created":"2023-07-26T01:11:57.321317+00:00","id":2001060,"links":{},"metadata":{"_buckets":{"deposit":"18d680f9-90d4-4210-86e8-68b5d39fb506"},"_deposit":{"created_by":4,"id":"2001060","owners":[4],"pid":{"revision_id":0,"type":"depid","value":"2001060"},"status":"published"},"_oai":{"id":"oai:niigata-u.repo.nii.ac.jp:02001060","sets":["453:455","471:561:562"]},"author_link":[],"item_6_date_granted_51":{"attribute_name":"学位授与年月日","attribute_value_mlt":[{"subitem_dategranted":"2023-03-23"}]},"item_6_degree_grantor_49":{"attribute_name":"学位授与機関","attribute_value_mlt":[{"subitem_degreegrantor":[{"subitem_degreegrantor_language":"ja","subitem_degreegrantor_name":"新潟大学"},{"subitem_degreegrantor_language":"en","subitem_degreegrantor_name":"Niigata 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(BANDDOS)に分類される。ALSPは成人期に発症するのに対し、BANDDOSは小児期に発症し重篤な臨床像を呈する。CSF1R関連白質脳症の遺伝子変異の大部分はCSF1Rチロシンキナーゼ領域に存在する。チロシンキナーゼ領域に存在するCSF1Rミスセンス変異は、リガンド依存性に誘導されるCSF1Rの自己リン酸化を消失させ、チロシンキナーゼ活性の喪失がALSPの病態機序の一因として考えられている。本研究はCSF1R関連白質脳症の分子病態機序を明らかにするために、リガンド依存性CSF1Rの自己リン酸化、CSF1Rのヘテロ2量体形成、変異型CSF1Rの顕性阻害効果について検討した。ALSPで報告されている顕性型バリアント、BANDDOSで報告されている潜性型バリアント、良性型バリアントを選抜し、発現コンストラクトを作製した。培養細胞にCSF1Rバリアントを一過性に発現させ、リガンド依存性に生じるCSF1Rの自己リン酸化を検討した。野生型CSF1Rではリン酸化CSF1Rが検出されたが、顕性型バリアントを発現する細胞では、リン酸化CSF1Rは検出されなかった。潜性型バリアントを発現する細胞では、リガンド刺激によるCSF1Rのリン酸化は減弱しているものの部分的に残存していた。良性型バリアントでは、CSF1Rのリン酸化は保たれていた。CSF1Rのリン酸化の程度は、CSF1R関連白質脳症の表現型と相関した。野生型と変異型CSF1Rを共発現させた実験では、両者のヘテロ2量体形成が示唆された。次に野生型CSF1Rを安定発現する細胞に、過剰な変異型CSF1Rを発現させ、顕性阻害効果を検証したところ、野生型CSF1Rのリン酸化の減弱は認めず、顕性阻害効果は否定的と考えられた。以上の結果から、CSF1Rのリン酸化を介したキナーゼ活性は、CSF1R関連脳症の臨床表現型と関連することが示唆された。","subitem_description_language":"ja","subitem_description_type":"Abstract"}]},"item_6_description_53":{"attribute_name":"学位記番号","attribute_value_mlt":[{"subitem_description":"新大院博(医)第1113号","subitem_description_language":"ja","subitem_description_type":"Other"}]},"item_6_dissertation_number_52":{"attribute_name":"学位授与番号","attribute_value_mlt":[{"subitem_dissertationnumber":"甲第5122号"}]},"item_access_right":{"attribute_name":"アクセス権","attribute_value_mlt":[{"subitem_access_right":"open 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